Brain Metastases After Complete Resection Of Primary Tumor Of Non-Small Cell Lung Cancer:Research On Tumor Molecular Pathological Features And Clinically Concerned Problems

Background:Regional lymph node metastases(LNMs)function as an important prognostic factor for non-small cell lung cancer(NSCLC)patients.However,its role in the development and progression of brain metastases(BMs)has not been well elucidated.Herein,we performed a multi-omics comparative study using paired BMs-LNMsprimary tumors(PTs)in NSCLC patients to explore the impact of regional LNMs on BM lesions.Methods:Parallel whole-transcriptome sequencing,targeted DNA and methylationsequencing were performed with paired surgical samples of PTs,BMs,and LNMs from 15 NSCLC patients.Multiple immunofluorescent assay(mIF)was also conducted with PT and BM samples.Patients were grouped into LNM(n=7)and non-LNM(n=8)according to the presence of regional LNM at the time of primary tumor resection.Results:LNMs revealed a methylation prolife distinctive from PT and BM lesions.The phylogenetic analysis showed that LNMs did not alter the evolutionary trajectories of BMs in 3/4 cases.PT lesions of the LNM group exhibited upregulation of tumor metastasis and progression relevant genes(KRT23,log2FC=4.20,p<0.001;IGF2BP3,log2FC=4.37,p=0.001)and pathways,and downregulation of neural transmitter and synaptic signaling signatures compared with PTs of the non-LNM group.More interestingly,BMs of the LNM group acquired higher expression of these neuron-like signatures than that of the non-LNM group(i.e.neuroactive ligand-receptor interaction,NSE=1.58,p=0.025)and less inflamed tumor microenvironment,characterized by reduced immune cell infiltration(M2 macrophages(p=0.028),NK cells(p=0.018),exhausted T cells(p=0.024)).Conclusions:Our results suggested that regional LNM had different impact on brain metastates.Brain metastases of LNM patients had more pronounced neuron-like properties with reduced immune cell infiltration.In contrast,brain metastases of patients without regional LNM had an opposite profile.Background:Patients with brain metastases only have better prognosis than those with synchronous extracranial metastases in non-small cell lung cancer(NSCLC).However,studies focusing on brain-only metastases after curative surgery remained scarce.This study aimed to explore distinct features of patients with exclusive brain metastases after resection of lung adenocarcinoma.Methods:Records were retrospectively reviewed of 2809 patients who had complete resection and pathologically confirmed stage ⅠB-ⅢA NSCLC in our hospital from October 2012 to September 2019.Patients were enrolled if they were adenocarcinoma and developed brain metastases thereafter.They were divided into two groups depending on whether they had synchronous extracranial metastases.Clinical and pathological features of patients enrolled were collected and compared between groups.Results:Ninety-seven lung adenocarcinoma patients with brain metastases were enrolled.The median follow-up time was 40 months.Fifty patients(51.5%)had brain metastases only and forty-seven patients had synchronous synchronous extracranial metastases(ECM).Multivariate logistic regression suggested EGFR-sensitive mutation and male sex were positively correlated to brain-only recurrence(OR=2.59,95%CI 1.04-6.84 and OR=2.58,95%CI 1.05-6.75),while higher clinical stage was associated with synchronous ECM(stage Ⅱ(OR=0.33,95%CI 0.09-1.14)or stage ⅢA(OR=0.54,95%CI 0.20-1.38)versus stage Ⅰ).No other pathological feature(lymphovascular invasion,visceral pleural invasion,low tumor differentiation,etc.)or adjuvant chemotherapy was associated with intracranial-only metastases after complete resection of primary tumor.Conclusion:Among patients with brain metastases after resection of lung adenocarcinoma,patients with EGFR mutations tent to have brain-only metastases without synchronous extracranial metastases.Further prospective studies are warranted to verify this.Background:Adjuvant chemotherapy(ACT)is considered for high-risk patients in stage ⅠB lung adenocarcinoma.However,these risk factors are recognized as negative prognostic factors,not as predictors of ACT benefit.This study retrospectively analyzed the impact of ACT in stage ⅠB patients who had recurrence/metastases(including brain metastases).Methods:We reviewed 1399 patient with stage ⅠB(AJCC 7th edition)lung adenocarcinoma from 2012 to 2017 in our institution and found 147 patients with recurrence.The last follow-up date was on Dec 30th,2021.One to one propensity-score matching(PSM)was used to reduce the potential selection bias.Results:55(37.4%)patients had received ACT and 92(62.6%)had not(non-ACT).Patients with ACT were younger(p<0.001),had larger tumor(p<0.001)and more lymphovascular invasion(p=0.02),and seemed to have less distant recurrence(p=0.001).After PSM,110 patients were matched and baseline characteristics were balanced.ACT was not associated with improved DFS after matching(mDFS=23.5m for ACT vs 29.5m for non-ACT,p=0.13).ACT failed to prolong DFS of patients in extracranial recurrence/metastases subgroup and EGFR mutation subgroups,and was even associated with shorter DFS in brain metastases patients(mDFS=30.3m vs 33.5m,p=0.083)and patients with tumor<=30mm(mDFS=21.9m vs 30.8m,p=0.076).Conclusion:In patients who had recurrence/metastases after completely resected stage IB lung adenocarcinoma,adjuvant chemotherapy might not be associated with improved DFS.Adjuvant chemotherapy might not be associated with improved DFS in brain metastases patients,either.Further large-scale multicenter studies are warranted to validate these findings.